Medications That Cause Elevated Potassium (Hyperkalemia)
Primary Culprits: RAAS Inhibitors
The most common drug-related causes of hyperkalemia are medications that inhibit the renin-angiotensin-aldosterone system (RAAS), including ACE inhibitors (e.g., lisinopril, enalapril), angiotensin receptor blockers/ARBs (e.g., losartan, valsartan), and direct renin inhibitors (aliskiren). 1, 2
- These medications impair renal potassium excretion by blocking aldosterone's effect on the distal nephron 3
- Risk increases substantially when combined with other potassium-elevating drugs, particularly in patients with chronic kidney disease (CKD) 1, 4
- ACE inhibitors may produce hyperkalemia particularly in patients with autonomic neuropathy, adrenal insufficiency, or renal impairment 5
Potassium-Sparing Diuretics and Aldosterone Antagonists
Spironolactone and eplerenone are high-risk medications that directly cause hyperkalemia by blocking aldosterone receptors in the kidney. 1, 4
- Spironolactone doses >25 mg daily significantly increase hyperkalemia risk 1, 6
- The FDA label explicitly warns that spironolactone can cause hyperkalemia, with risk increased by impaired renal function or concomitant potassium supplementation 4
- In the RALES trial, hyperkalemia was uncommon in controlled settings but occurs more frequently in clinical practice, especially in elderly patients 1
- Other potassium-sparing diuretics (amiloride, triamterene) also cause hyperkalemia by the same mechanism 1
NSAIDs and Related Medications
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause hyperkalemia by impairing renal potassium excretion through prostaglandin inhibition. 3, 5
- NSAIDs may occasionally produce hyperkalemia, particularly in patients with renal impairment or when combined with ACE inhibitors 5
- The combination of NSAIDs with RAAS inhibitors creates synergistic risk 4
Antimicrobial Agents
Trimethoprim-sulfamethoxazole causes hyperkalemia through a unique mechanism: trimethoprim blocks the epithelial sodium channel (ENaC) in the distal nephron, mimicking amiloride's effect. 1, 7
- The FDA label specifically warns that trimethoprim may cause hyperkalemia when administered to patients with underlying potassium metabolism disorders, renal insufficiency, or when given with drugs that induce hyperkalemia such as ACE inhibitors 7
- Close monitoring of serum potassium is warranted, and discontinuation is recommended to lower potassium levels 7
- Pentamidine also impairs renal potassium excretion 3
Immunosuppressants
Calcineurin inhibitors (cyclosporine, tacrolimus) cause hyperkalemia by impairing renal potassium excretion. 1, 3
Anticoagulants
Heparin and low-molecular-weight heparin cause hyperkalemia by suppressing aldosterone synthesis in the adrenal gland. 1, 4, 3
Sacubitril-Valsartan
This combination angiotensin receptor-neprilysin inhibitor (ARNI) carries hyperkalemia risk due to its ARB component. 1
High-Risk Clinical Scenarios
The following combinations and patient factors dramatically increase hyperkalemia risk and require intensive monitoring: 1, 6
- Combination therapy: ACE inhibitor/ARB + spironolactone/eplerenone is particularly dangerous 1, 6
- Renal insufficiency: CKD with CrCl <30 mL/min or serum creatinine >2.5 mg/dL 1
- Elderly patients (age >65-75 years) 6
- Diabetes mellitus 6
- Dehydration or acute illness 6, 8
- Potassium supplements or salt substitutes 4
Monitoring Requirements
When prescribing hyperkalemia-inducing medications, check serum potassium within 1 week of initiation or dose titration, then at 1,2,3, and 6 months, and every 6 months thereafter. 1, 4
- Halt spironolactone/eplerenone if potassium rises to 6.0 mmol/L 1
- Halve the dose if potassium rises to 5.5 mmol/L 1
- More frequent monitoring is needed when combining multiple hyperkalemia-inducing drugs 4
Medications That Do NOT Cause Hyperkalemia
The following commonly used cardiovascular medications have no association with hyperkalemia: 2